Preparation method of isochromanone compound
By using N-hydroxyphthalimide catalyst and oxygen oxidant in microchannel reactors, the problems of toxic oxidants and metal catalysts in the existing heterochromatic ketone synthesis methods are solved, and high yield and high purity are achieved. Preparation of heterochromatic ketones has good industrial application prospects.
Patent Information
- Application Number
- CN202411451479.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-17
- Publication Date
- 2025-01-07
AI Technical Summary
The existing heterochromatic ketone synthesis methods have problems such as the use of toxic and harmful oxidants, many reaction steps, harsh conditions and low product yields, and metal catalysts are expensive and complex in structure.
N-hydroxyphthalimide as catalyst, tert-butyl nitrite as initiator, oxygen as oxidant, and reaction in microchannel reactor, molecular oxygen as oxidant, avoiding metal ion residues and strong acid catalysis , improves the mildness and yield of the reaction conditions.
The preparation of heterochromatic ketones with high yield, low cost and pollution-free by-products has been achieved, the reaction steps are simplified, the product purity is improved, and the industrial application prospects are good.
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Figure CN119264096A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing an isochromanone compound. Background Art
[0002] Organic compounds containing isochromanone (six-membered ring lactone) structural units are important components of many natural products and active pharmaceutical molecules. Therefore, the research on the synthesis methods of such compounds has attracted widespread attention from many research groups at home and abroad. However, the existing isochromanone synthesis strategies often involve multi-step synthesis of raw materials or the use of relatively dangerous CO gas or strong acid, which greatly limits the application of these methods.
[0003] For example, Professor Caubere et al. used octacarbonyl dicobalt as the carbonylation reagent instead of dangerous carbon monoxide gas to react with o-bromophenylethanol to undergo carbonylation cyclization reaction, and successfully achieved the synthesis of isochromanone. However, benzene, which is highly harmful to the human body, was required as the reaction solvent in the reaction, and the reaction had to be carried out under strong alkaline conditions. Yu Jinquan et al. used benzoic acid and 1,2-dichloroethane as raw materials, and successfully achieved the synthesis of isochromanone through nucleophilic substitution / Heck coupling tandem reaction under the catalysis of palladium acetate. Toma et al. used 3 equivalents of potassium permanganate as the oxidant, copper sulfate pentahydrate as the carrier of potassium permanganate, dichloromethane as the solvent, and the reaction temperature was room temperature. The results showed that in the presence of ultrasound, isochromanone can be synthesized in a relatively short time (2 h) was completely converted into isochromanone, while in the control group without ultrasound, only 14% of isochromanone was converted in the same period of time. This method has a short reaction time and a high yield, but requires ultrasound as an auxiliary condition; StrazzoLini et al. used 3 equivalents of nitric acid as an oxidant and dichloromethane as a solvent to prepare isochromanone by benzylic oxidation at room temperature.
[0004] With the development of modern organic synthesis methods, people can now synthesize isochromanones through various methods. However, traditional synthesis methods have problems such as the need for toxic and harmful oxidants, multiple reaction steps, harsh reaction conditions, and low product yields. In recent years, oxygen, as a clean and economical oxidant, has been applied to the benzylic oxidation of isochromanones and heteroanthracenes and has become a hot topic of research. However, these methods still have some disadvantages: (1) The catalysts are expensive. In metal-catalyzed reaction systems, organic compounds with complicated synthesis methods and complex structures are usually required as ligands; (2) Some reactions require higher reaction temperatures to proceed; (3) Some reactions have low activity and low product yields.
[0005] Therefore, it is necessary to provide a method for preparing an isochromanone compound. Summary of the invention
[0006] The purpose of the present invention is to solve the deficiencies of the prior art and to provide a new method for preparing an isochromanone compound.
[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows: A method for preparing an isochromanone compound comprises the following steps: using isochromanone as a raw material, N-hydroxyphthalimide as a catalyst, tert-butyl nitrite as an initiator, and oxygen as an oxidant, and reacting in a microchannel reactor in the presence of an organic solvent to generate isochromanone, and the reaction route is as follows: .
[0008] Furthermore, the molar ratio of the initiator, the catalyst and the isochroman is 0.25-0.5:0.06-0.2:1.
[0009] Furthermore, the organic solvent is any one of dichloromethane, ethanol, acetonitrile, ethyl acetate or methanol.
[0010] Furthermore, during the reaction, the screening range of the flow rate of the liquid phase pump in the microchannel reactor is 1.0 mL / min~2.0 mL / min.
[0011] Furthermore, during the reaction, the screening range of the gas flow meter flow rate in the microchannel reactor is 10.0 mL / min~40.0 mL / min.
[0012] Furthermore, the temperature during the reaction is 60°C to 120°C.
[0013] Furthermore, according to the method for preparing isochromanone according to claim 1, it is characterized in that the reaction time is 34s-127s.
[0014] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention uses N-hydroxyphthalimide and tert-butyl nitrite as a catalytic oxidation system, which can ensure a high yield while making the reaction conditions milder. It also overcomes the problems of introducing metal ions and using strong acid catalytic oxidation in traditional processes. The product has high purity and has good prospects for industrial application.
[0015] 2. In the present invention, molecular oxygen is used as the oxidant, which is cheap and easily available, has good atom economy, and has no pollution from byproducts; the catalyst uses an organic catalyst N-hydroxyphthalimide, which is different from a metal catalyst, is relatively cheap, and does not leave any metal ions in the product, is not easily deactivated, and has better catalytic performance.
[0016] 3. The microchannel reactor used in the present invention has the characteristics of high heat transfer and high mass transfer efficiency, providing a new approach to solving the problems of low efficiency of oxidation reaction, poor atomic economy of oxidant, high safety risk and difficulty in scale-up. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 It is the liquid chromatogram of Example 1 of the present invention; Figure 2 It is the liquid chromatogram of Example 2 of the present invention; Figure 3 It is the liquid chromatogram of Example 3 of the present invention; Figure 4 It is the liquid chromatogram of Example 4 of the present invention; Figure 5 It is the liquid chromatogram of Example 5 of the present invention; Figure 6 It is the liquid chromatogram of Example 6 of the present invention; Figure 7 is the liquid chromatogram of Example 7 of the present invention; Figure 8 is the liquid chromatogram of Example 8 of the present invention; Fig. 9 is the liquid chromatogram of Example 9 of the present invention; Fig.10 is the liquid chromatogram of Example 10 of the present invention; Fig.11 is the liquid chromatogram of Example 11 of the present invention; Fig.12 is the liquid chromatogram of Example 12 of the present invention; Fig.13 is the liquid chromatogram of Example 13 of the present invention; Fig.14 is the liquid chromatogram of Example 14 of the present invention; Fig.15 is the liquid chromatogram of Example 15 of the present invention; Fig.16 This is the liquid chromatogram of Example 16 of the present invention. DETAILED DESCRIPTION
[0018] The present invention is further described in detail below in conjunction with embodiments.
[0019] Those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, they are carried out according to the techniques or conditions described in the literature in this area or according to the product instructions. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased.
[0020] The manufacturer of the microchannel reactor used in the present invention is Shandong Haomai Machinery Manufacturing Co., Ltd., model: RMHS1210, and the microchannel reactor is equipped with a liquid phase pump and a gas flow meter.
[0021] Example 1
[0022] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent acetonitrile to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 °C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.088 g of pure product.
[0023] Liquid chromatography analysis showed that the product peak was at around 11.20 min, with a reaction conversion rate of 75.24% and a yield of 67.08%.
[0024] Full conversion rate of heterochromatic color =
[0025] In the formula: c0 is the amount of the heterochromatic substance before the reaction, mol; c1 is the amount of the heterochromatic substance after the reaction, mol.
[0026] Yield of isochromanone =
[0027] Example 2
[0028] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 ° C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.136 g of pure product.
[0029] Liquid chromatography analysis showed that the peak position was around 11.03 min, the reaction conversion rate was 98.34%, and the yield was 95.86%.
[0030] Example 3
[0031] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethanol to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 °C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.045 g of pure product.
[0032] Liquid chromatography analysis showed that the peak position was around 11.12 min, the reaction conversion rate was 38.26%, and the yield was 35.47%.
[0033] Example 4
[0034] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI into the sample bottle, and add 12 mL of solvent dichloromethane to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 °C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.053 g of pure product.
[0035] Liquid chromatography analysis showed that the peak position was around 11.15 min, the reaction conversion rate was 42.82%, and the yield was 38.85%.
[0036] Example 5
[0037] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent methanol to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 ° C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.048 g of pure product.
[0038] Liquid chromatography analysis showed that the peak position was around 11.19 min, the reaction conversion rate was 39.58%, and the yield was 37.26%.
[0039] Example 6
[0040] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 70 ° C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.091 g of pure product.
[0041] Liquid chromatography analysis showed that the peak position was around 11.26 min, the reaction conversion rate was 73.27%, and the yield was 65.84%.
[0042] Example 7
[0043] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI into the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 60 ° C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.012 g of pure product.
[0044] Liquid chromatography analysis showed that the peak position was around 11.19 min, the reaction conversion rate was 12.14%, and the yield was 10.98%.
[0045] Example 8
[0046] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI into the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 120 ° C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0.041 g of pure product.
[0047] Liquid chromatography analysis showed that the peak position was around 11.24 min, the reaction conversion rate was 94.32%, and the yield was 31.34%.
[0048] Example 9
[0049] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the nitrogen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 ° C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0 g of pure product.
[0050] Analysis by liquid chromatography showed that basically no product peak appeared around 11 minutes, and the yield was 0.
[0051] Example 10
[0052] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 2.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 °C, and the reaction time is 63 s. After the reaction is completed, vacuum distillation is performed to obtain 0.109 g of pure product.
[0053] Liquid chromatography analysis showed that the peak position was around 11.24 min, the reaction conversion rate was 83.27%, and the yield was 76.89%.
[0054] Embodiment 11
[0055] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.5 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 ° C, and the reaction time is 65 s. After the reaction is completed, vacuum distillation is performed to obtain 0.115 g of pure product.
[0056] Liquid chromatography analysis showed that the peak position was around 11.20 min, the reaction conversion rate was 85.67%, and the yield was 80.35%.
[0057] Example 12
[0058] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 30.0 mL / min, the reaction temperature in the microchannel reactor is 100 °C, and the reaction time is 45 s. After the reaction is completed, vacuum distillation is performed to obtain 0.121 g of pure product.
[0059] Liquid chromatography analysis showed that the peak position was around 11.10 min, the reaction conversion rate was 85.79%, and the yield was 83.77%.
[0060] Embodiment 13
[0061] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 10.0 mL / min, the reaction temperature in the microchannel reactor is 100 ° C, and the reaction time is 127 s. After the reaction is completed, vacuum distillation is performed to obtain 0.076 g of pure product.
[0062] Liquid chromatography analysis showed that the peak position was around 11.25 min, the reaction conversion rate was 87.94%, and the yield was 56.35%.
[0063] Embodiment 14
[0064] Add 0.134 g of isochroman, 0.025 g of initiator TBN, 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 40.0 mL / min, the reaction temperature in the microchannel reactor is 100 ° C, and the reaction time is 34 s. After the reaction is completed, vacuum distillation is performed to obtain 0.072 g of pure product.
[0065] Liquid chromatography analysis showed that the peak position was around 11.24 min, the reaction conversion rate was 54.53%, and the yield was 50.35%.
[0066] Embodiment 15
[0067] Add 0.134 g of isochroman and 0.0102 g of catalyst NHPI to the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 ° C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0 g of pure product.
[0068] Liquid chromatography analysis showed that basically no product peak appeared around 11 minutes, and the reaction yield was 0.
[0069] Example 16
[0070] Add 0.134 g of isochroman and 0.025 g of initiator TBN into the sample bottle, and add 12 mL of solvent ethyl acetate to dissolve, the liquid phase pump flow rate is 1.0 mL / min, the oxygen flow rate is 20.0 mL / min, the reaction temperature in the microchannel reactor is 100 °C, and the reaction time is 66 s. After the reaction is completed, vacuum distillation is performed to obtain 0 g of pure product.
[0071] Liquid chromatography analysis showed that basically no product peak appeared around 11 minutes, and the reaction yield was 0.
[0072] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned comparative examples, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing an isochromanone compound, characterized in that: The method comprises the following steps: using isochroman as a raw material, N-hydroxyphthalimide as a catalyst, tert-butyl nitrite as an initiator, and oxygen as an oxidant, and reacting in a microchannel reactor in the presence of an organic solvent to generate isochromanone. The reaction route is as follows: 。 2. The method for preparing isochromanone according to claim 1, characterized in that: The molar ratio of the initiator, the catalyst and the isochroman is 0.25-0.5:0.06-0.2:
1.
3. The method for preparing isochromanone according to claim 1, characterized in that: The organic solvent is one of dichloromethane, ethanol, acetonitrile, ethyl acetate or methanol.
4. The method for preparing isochromanone according to claim 1, characterized in that: During the reaction, the screening range of the flow rate of the liquid phase pump in the microchannel reactor is 1.0 mL / min~2.0 mL / min.
5. The method for preparing isochromanone according to claim 1, characterized in that: During the reaction, the screening range of the gas flow meter flow rate in the microchannel reactor is 10.0 mL / min~40.0 mL / min.
6. The method for preparing isochromanone according to claim 1, characterized in that: The temperature during the reaction is 60°C to 120°C.
7. The method for preparing isochromanone according to claim 1, characterized in that: The reaction time is 34s-127s.